Derivatives of 8-pyridone [5,6 g] quinoline, pharmaceutical composition and methods of using them

 

Describes new derivatives of 8-pyridone [5,6 g]quinoline of formula (I), or (III) or (IV), where R1is hydrogen, fluorine, chlorine, bromine, iodine, R2- CF3-CF2H, R3is hydrogen, R4and R5each independently hydrogen or C1-C4-alkyl, R6and R7is hydrogen, R8is hydrogen, C1-C4-alkyl, R9- R18- each hydrogen, R19- fluorine or NO2, R24is hydrogen, C1-C4-alkyl, NO2, R25is hydrogen, C1-C4-alkyl, R26is hydrogen, C1-C6-alkyl, R27and R28each independently hydrogen or C1-C4-alkyl, m is 1, n is 0 or 1, o is 0 or 1, Y Is O, Z is NH, NR22, R22- C1-C4-alkyl, and pharmaceutical composition for influencing the activity androgenetic receptors. Describes a way of influencing the activity androgenetic receptor, the method of modulating a process mediated androgenicity receptors, the method of treatment of a patient, comprising the modulation process, mediated androgenicity receptors, a method of treating a patient in need of androgen-receptor therapy that uses derivatives of 8-pyridone[5,6 g] quinoline. The technical result to sabatica in the treatment and/or modulation of acne, male pattern baldness, hirsutism, hypogonadism, prostatic hyperplasia, as well as hormone-dependent cancers. 6 C. and 30 C.p. f-crystals, 4 PL.

Description text in facsimile form (see graphic part)and

Claims

1. Derivatives of 8-pyridone [5,6 g] quinoline of formulaororwhere R1represents hydrogen, F, Cl, Br, I;
R2is a CF3, CF2H;
R3represents hydrogen;
R4and R5each independently represents hydrogen or C1-C4alkyl;
R6and R7represent hydrogen;
R8represents hydrogen or C1-C4alkyl;
R9-R18each independently represents hydrogen;
R19represents F or NO2;
R24represents hydrogen, C1-C4alkyl or NO2;
R25represents hydrogen, C1-C4alkyl;
R26is hydrogen, C1-C6Alki the
n is 0 or 1;
o is 0 or 1;
Y is O;
Z represents NH, NR22where R22is1-C4the alkyl.

2. Derivatives under item 1, in which in the compound of formula III, R3, R4, R5, R6, R7, R24and R26are hydrogen, and m is 1.

3. Derivatives under item 2, in which R8and R25are CH3.

4. Derivatives under item 3, in which Z is NH.

5. Derivatives under item 4, in which R19is F.

6. Derivatives under item 5, in which R2is CF3.

7. Derivatives PP. 1-6, and derivatives are modulators androgenetic receptors.

8. Derivatives under item 7, and derivatives are antagonists androgenetic receptors.

9. Derivatives under item 7, and derivatives are agonists androgenetic receptors.

10. Derivatives under item 7, where the derivatives are partial agonists androgenetic receptors.

11. Derivatives under item 7, selected from the group consisting of
(R/S)-6,7,7 a,11-tetrahydro-7a-methyl-4-trifluoromethyl-2-pyridone[5,6-g]pyrrolidino[1,2-a]quinoline;
(R/S)-3-fluoro-6,7,7 a, 11-tetrahydro-7a-methyl-4-trifluoromethyl-2-pyridone[5,6-g]pyrrolidino[1,2-a]quinoline;
(R/S)-6,7,7 a,11-tetrahydro-1,7-dimethyl-4-cryptogon[5,6-g]pyrrolidino[1,2-a]quinoline;
11-(trifluoromethyl)-9-pyridone[6,5-i]julolidine;
8-methyl-11-(trifluoromethyl)-9-pyridone[6,5-i]julolidine;
7-fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridone[5,6-g] quinoline;
6-deformity-7-fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-8-pyridone[5,6-g] quinoline;
7-fluoro-1,2,3,4-tetrahydro-2,2,9-trimethyl-6-trifluoromethyl-8-pyridone-[5,6-g]quinoline;
6-deformity-7-fluoro-1,2,3,4-tetrahydro-2,2,9-trimethyl-8-pyridone-[5,6-g]quinoline;
7-fluoro-1,2,3,4-tetrahydro-1,2,2,9-tetramethyl-6-trifluoromethyl-8-pyridone-[5,6-g]quinoline;
6-deformity-7-fluoro-1,2,3,4-tetrahydro-1,2,2,9-tetramethyl-8-pyridone[5,6-g]quinoline;
7-fluoro-1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyridone[5,6-g]-quinoline;
7-fluoro-1,2,3,4-tetrahydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyridone-[5,6-g]quinoline;
1,10-[1,3-dihydro-3-oxo-(2,1-isoxazolyl)] -1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridone[5,6-g]quinoline;
7-fluoro-1,2-dihydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridone[5,6-g] quinoline;
7-fluoro-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridone[5,6-g]quinoline;
7-fluoro-1,2,3,4-tetrahydro-2,2,4,9,10-pentamethyl-6-trifluoromethyl-8-pyridone[5,6-g]quinoline;
7-fluoro-1,2,3,4-tetrahydro-1,2,2,4,10-pentamethyl-6-trifluoromethyl-8-pyridone[5,6-g]quinoline;
2,2-diethyl-7-fluoro-1,2,3,4-tetrahydro-6-trifluoromethyl-8-pyridone[5,6-g] -China composition for influencing the activity androgenetic receptors containing derivatives according to any one of paragraphs.1-6 effective for this dose and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to p. 12, in which in the compound of formula III, R3, R4, R5, R6, R7, R24and R26are hydrogen.

14. The pharmaceutical composition according to p. 13, in which R8and R25are CH3.

15. The pharmaceutical composition according to p. 14, in which Z is NH.

16. The pharmaceutical composition according to p. 15, in which R19is F.

17. The pharmaceutical composition according to p. 16, in which R2is CF3.

18. The pharmaceutical composition according to paragraphs.12-17, characterized in that it is made in the form of a preparation for oral, local, intravenous, suppozitornyj or parenteral administration.

19. The pharmaceutical composition according to paragraphs.12-17, characterized in that the compound is administered to the patient in a standard dose of 1 µg/kg body weight to 500 mg/kg of body weight.

20. The pharmaceutical composition according to paragraphs.12-17, characterized in that the compound is administered to the patient in a standard dose of 10 mg/kg of body weight up to 250 mg/kg of body weight.

21. The pharmaceutical composition according to paragraphs.12-17, characterized in that the compound is administered to the patient in V7, characterized in that the composition is effective in the treatment and/or modulation of acne, male pattern baldness, hirsutism, hypogonadism, prostatic hyperplasia, as well as hormone-dependent cancers, such as prostate cancer and breast cancer.

23. The pharmaceutical composition according to paragraphs.12-17, characterized in that it has little effect as anabolic agent.

24. The way to influence the activity androgenetic receptors, when injected in vivo connection PP.1-6.

25. The method according to p. 24, in which in the compound of formula III, R3, R4, R5, R6, R7, R24and R26are hydrogen.

26. The method according to p. 25, in which R8and R25are CH3.

27. The method according to p. 26, in which Z is NH.

28. The method according to p. 27, in which R19is F.

29. The method according to p. 28, in which R2is CF3.

30. The method according to p. 24, wherein the specified compound is administered in the form of a pharmaceutical composition in a pharmaceutically acceptable carrier, and the composition is a composition under item 12.

31. The method of modulating a process mediated androgenicity receptors, wherein the patient is administered an effective amount of a compound according to any one of paragraphs.1-6.

33. A method of treating a patient comprising modulating process, mediated androgenicity receptors, wherein the patient is administered an effective amount of a compound according to any one of paragraphs.1-6.

34. The method of treatment of a patient by p. 33, characterized in that the compound is effective in the treatment and/or modulation of acne, male pattern baldness, hirsutism, hypogonadism, prostatic hyperplasia, as well as hormone-dependent cancers, such as prostate cancer and breast cancer.

35. A method of treating a patient in need of androgenreceptor therapy in which a given patient is administered an effective amount of a compound according to any one of paragraphs.1-6.

36. The method of treatment of a patient by p. 35, characterized in that the compound is effective in the treatment and/or modulation of acne, male pattern baldness, hirsutism, hypogonadism, prostatic hyperplasia, as well as hormone-dependent cancers, such as prostate cancer and breast cancer.

 

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